Pyrrolophenothiazine carboxamides

ABSTRACT

Compounds of the formula ##STR1## wherein the broken line represents an optional double bond; X is O, S, CH 2  or CH 2  CH 2 , and the pharmaceutically acceptable salts thereof. The compounds are useful in treating inflammation or other prostaglandin or leukotriene mediated diseases.

BACKGROUND OF THE INVENTION

The present invention relates to pyrroloquinoline andpyrrolophenothiazine carboxamides and related compounds, methods ofpreparing such compounds, pharmaceutical compositions comprising suchcompounds and the use of such compounds in treating inflammation (e.g.,arthritis) or other prostaglandin or leukotriene mediated diseases.

Oxindole-carboxamides useful as antiinflammatory agents and analgesicsare referred to in U.S. Pat. Nos. 4,556,672, 4,569,942, 4,644,005,4,678,802, and 4,686,224, and in U.S. Ser. No. 670,697, filed Nov. 13,1984, and U.S. Ser. No. 821,296, filed Jan. 22, 1986.

U.S. Pat. No. 4,695,571 refers to tricyclic oxindoles asantiinflammatory agents.

United States Patent 4,690,943 refers to 1,3-diacyl-2-oxindoles asantiinflammatory agents and analgesics.

U.S. Pat. No. 4,658,037 and U.S. Ser. No. 670,697, filed Nov. 13, 1984,refer to intermediates for preparing oxindole carboxamides.

SUMMARY OF THE INVENTION

The present invention relates to compounds of the formula ##STR2##wherein the broken line represents an optional double bond; X is O, S,CH₂ or CH₂ CH₂ ; R is selected from the group consisting of hydrogen,halogen (e.g., fluorine, chlorine, bromine and iodine), C₁ -C₆ alkoxy(e.g., OCH₃) , C₁ -C₆ alkanoyl, C₁ -C₆ alkyl, and trifluoromethyl; R² isselected from the group consisting of phenyl, substituted phenyl,heterocyclic groups, and substituted heterocyclic groups, saidsubstituted phenyl and substituted heterocyclic groups being substitutedwith 1 or 2 substituents independently selected from the groupconsisting of C₁ -C₆ alkyl, trifluoromethyl, and halogen (e.g. fluorine,chlorine, bromine and iodine);

R³ and R⁴ are independently selected from the group consisting ofhydrogen, halogen (e.g., fluorine, chlorine, bromine and iodine), C₁ -C₆alkyl, and trifluoromethyl, or R³ and R⁴, taken together with the carbonatoms to which they are attached, form a six-membered carbocyclicaromatic ring, said aromatic ring being optionally substituted with oneor two substituents selected from the group consisting of halogen (e.g.,fluorine, chlorine, bromine or iodine), C₁ -C₆ alkyl, andtrifluoromethyl; and the pharmaceutically acceptable salts thereof. The"floating bond" in formula I is intended to indicate that R¹ may beconnected to any one of positions a, b and c of the aromatic ring.Position b is preferred. When R² is a heterocyclic group, R² ispreferably selected from benzothiazole, isoxazole, isothiazole, oxazole,pyridine, thiazole and thiadiazole. The foregoing heterocyclic groupsmay be substituted as described above.

The present invention also relates to a pharmaceutical compositionuseful in the treatment of inflammation or other prostaglandin orleukotriene mediated diseases comprising an amount of a compound of theformula I effective to treat inflammation or another prostaglandin orleukotriene mediated disease and a pharmaceutically acceptable carrier.

The present invention also relates to a method of treating aprostaglandin or leukotriene mediated disease comprising administeringto a patient in need of such treatment a compound of formula I in anamount effective to treat such disease.

The present invention also relates to intermediates useful in preparingthe foregoing compounds and to methods of preparing the foregoingcompounds.

A preferred embodiment of the present invention relates to compounds ofthe formula ##STR3## wherein R¹, R² and X are as defined above and R⁵ isselected from the group consisting-of hydrogen, halogen, C₁ -C₆ alkyl,and trifluoromethyl, and the pharmaceutically acceptable salts thereof.More preferably R¹ is hydrogen or fluorine; R² is phenyl,2,4-difluorophenyl, pyridinyl, thiazolyl, benzothiazolyl, isothiazolyl,or isoxazolyl, and R⁵ is hydrogen or fluorine.

Another preferred embodiment of the present invention relates tocompounds of the formula ##STR4## wherein R¹, R², R³ and X are asdefined above, and the pharmaceutically acceptable salts thereof. Morepreferably, R¹ is hydrogen, fluoro, or trifluoromethyl; R² is phenyl,2,4-difluorophenyl, pyridyl, thiazolyl, isothiazolyl, benzothiazolyl orisoxazolyl; R³ is hydrogen, fluoro, or trifluoromethyl; and X is O, S orCH₂.

Another preferred embodiment of the present invention relates tocompounds of the formula ##STR5## wherein R¹, R², R³, R⁴ and X are asdefined above, with the proviso that R³ and R⁴ do not form a carbocyclicaromatic ring, and the pharmaceutically acceptable acid addition saltsthereof. More preferably, R¹ is hydrogen and X is S. Most preferably, R¹is hydrogen, R³ is trifluoromethyl, R⁴ is fluorine and X is S.

In each of the foregoing preferred embodiments, it is more preferredthat R¹ be connected to position b of the aromatic ring.

Specific preferred compounds of the present invention include thefollowing:

1,2-dihydro-N-phenyl-1-oxopyrrolo[3,2,1-kl]phenothiazine-2-carboxamide;

1,2-dihydro-N-(2,4-difluorophenyl)-1-oxopyrrolo[3,2,1-kl]phenothiazine-2-carboxamide;

1,2-dihydro-N-(2-pyridyl)-1-oxopyrrolo[3,2,1-kl]-phenothiazine-2-carboxamide;

1,2-dihydro-N-(2-thiazolyl]-1-oxopyrrolo[3,2,1-kl]-phenothiazine-2-carboxamide;

1,2-dihydro-N-phenyl-1-oxopyrrolo[3,2,1-kl]-phenoxazine-2-carboxamide;

1,2-dihydro-N-(2-pyridyl)-1-oxopyrrolo[3,2,1-kl]-phenoxazine-2-carboxamide;

N-(2-thiazolyl)-6H-pyrrolo[3,2,1-de]acridin-1(2H)-one-2-carboxamide;

N-(5-methyl-thiazolyl-2)-6H-pyrrido[3,2,1-de]-acridin-1(2H)-one-2-carboxamide;

N-(thiazolyl-2)-4-fluoro-6H-pyrrido[3,2,1-de]-acridin-1(2H)-one-2-carboxamide;

5-oxo-N-(2-thiazolyl)pyrrolo[1,2,3-de]-tetrahydro-1,4-benzothiazine-6-carboxamide;

2-oxo-N-(2-thiazolyl)-8-fluoro-4H-pyrrolo-3,2,1-ij]quinoline-1-carboxamide;and

5,6-dihydro-2-fluoro-5-oxo-N-(2-thiazolyl)-3-trifluoromethylpyrrolo[1,2,3-de]-1,4-benzothiazine-6-carboxamide.

Preferred compositions of the present invention include the foregoingpreferred and specific preferred compounds.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of the present invention may be prepared as described inthe following reaction scheme: ##STR6##

In the foregoing reaction scheme, R¹, R², R³ and R⁴ are as definedabove.

The compound of the formula V is reacted in an inert solvent withClCOCH₂ Cl to provide the compound of formula VI. Either or bothchlorine atoms in the compound of formula VI may be replaced by abromine atom. The solvent is preferably an aromatic hydrocarbon such asbenzene or toluene or a halohydrocarbon such as methylene chloride orchloroform. The temperature is not critical and generally ranges fromabout 20° C. to about 120° C. Preferably, the temperature is the refluxtemperature of the solvent.

The compound of the formula VII is generally obtained by fusion of thecompound of formula VI with anhydrous AlCl₃ at a temperature within afew degrees of the melting point of the compound of formula VI, using atemperature no greater than about 200° C.

The compound of the formula VII is reacted in an alcoholic solvent,preferably a C₁ -C₄ alcohol, or an aprotic polar solvent (e.g.,dimethylformamide (DMF)) with a base such as sodium hydride, sodium C₁-C₄ alkoxide or potassium C₁ -C₄ alkoxide and with dialkylcarbonate oralkylchloroformate wherein the alkyl groups may contain 1 to 4 carbonatoms, preferably 1 or 2 carbon atoms, to provide the compound offormula VIII wherein R⁶ is C₁ -C₄ alkyl, preferably C₁ -C₄ alkyl. Thetemperature is not critical and generally ranges from about 0° C. toabout 100° C. Preferably, the temperature is the reflux temperature ofthe solvent.

In order to prepare a compound of the formula I, the compound of theformula VII is reacted in an inert solvent in the presence of a basesuch as sodium hydride or potassium hydride with a compound of theformula R² N═C═O wherein R² is as defined above. The solvent ispreferably DMF or diglyme. The temperature is not critical and generallyranges from about 0° C. to about 30° C. The temperature is preferablyroom temperature (about 22° C.).

The compound of the formula I may also be prepared by reacting acompound of the formula VIII, wherein R⁶ is as defined above, with acompound of the formula R² NH₂ in an inert solvent The solvent ispreferably toluene or xylene. The temperature is not critical andgenerally ranges from about 100° C. to about 200° C. The temperature ispreferably the reflux temperature of the solvent.

The pressure used in each of the foregoing reactions is not critical.Generally, a pressure of about 0.5 to about 2 atmospheres, preferablyambient pressure (about one atmosphere) will be used.

Salts of compounds of the formula I may be prepared in a conventionalmanner by reacting a compound of the formula I with an appropriate base,for example, an inorganic base such as an alkali metal hydroxide or analkaline earth metal hydroxide.

The activity of the compounds of formula I in the treatment ofpulmonary, asthmatic, allergic and inflammatory diseases may bedetermined by a standard test measuring an agent's ability to inhibitcyclooxygenase and 5-lypoxygenase enzyme activity of rat basophilleukemia (RBL-1) cells. According to this test as described by Jakschicket al., Prostaglandins, 16,733-747 (1978), and Jakschick et al.,Biochem. Biophys. Res. Commun., 95, 103-110 (1980), a monolayer of RBL-1cells is grown for 1 or 2 days in spinner culture in Eagle's minimumessential medium, 15% heat-inactivated fetal calf serum and anantibiotic/antimycotic mixture. The cells are washed aftercentrifugation and incubated in a buffer. A volume of 0.5 ml of cellsuspension is preincubated at 30° C. for ten minutes with a 1 microliterdimethylsulfoxide (DMSO) solution of the agent to be tested. Theincubation is initiated by simultaneous addition of 5 microliters (¹⁴C)-arachidonic acid in ethanol and 2 microliters calcium ionophore(A-21387) in DMSO for final concentrations of 5 and 7.6 micromolar,respectively. Five minutes later, the incubation is terminated by theaddition of 0.27 ml acetonitrile/acetic acid (100:3). High pressureliquid chromatography is performed using acetonitrile/water/acetic acidsolvent. Radiolabeled prostaglandin D₂ (PGD₂), leukotrine B₄ (LTB₄),5-hydroxyeicosatetraenoic acid (5-HETE), and unreacted arachidonic acidare determined. The inhibitory effect on the cyclooxygenase pathway isassessed from the reduction of PGD₂ levels and the inhibitory effect onthe 5-lipoxygenase pathway is assessed from the decrease in the amountof LTB₄ and 5-HETE.

The compounds of the formula I and their pharmaceutically acceptablesalts are effective inhibitors of mammalian leukotriene or prostaglandinbiosynthesis or both and are thus useful in the treatment of variousleukotriene or prostaglandin mediated conditions. In particular, thecompounds have utility, both as the sole active agent and also incombination with other active agents, for the treatment of variouspulmonary, gastrointestinal, inflammatory, dermatological andcardiovascular conditions such as inflammation, arthritis, allergy,psoriasis, asthma, bronchitis, pulmonary hypertension and hypoxia,peptic ulcers, inflammatory bowel disease or cardiovascular spasm, suchas acute myocardial infarctions, and the like in mammals, especially inhumans. The compounds of the formula I and their pharmaceuticallyacceptable salts are particularly useful in treating arthritis.

For treatment of the various conditions described above, the compoundsof formula I and their pharmaceutically acceptable salts may beadministered to a subject in need of treatment by a variety ofconventional routes of administration, including oral, by injection,topical, rectal, and in an aerosol carrier composition foradministration by inhalation.

The exact dosage of a compound of the present invention will depend uponsuch factors as the age, weight and condition of the patient and theseverity of disease. In general, however, a therapeutically effectivedose of a compound of formula I or a pharmaceutically acceptable saltthereof will range from 0.1 to 25 mg/kg body weight of the subject to betreated per day, preferably 0.5 to 10 mg/kg per day.

Although the compounds of formula I and their pharmaceuticallyacceptable salts can be administered alone, they will generally beadministered in admixture with a pharmaceutical carrier selected withregard to the intended route of administration and standardpharmaceutical practice. For example, oral administration may be in theform of tablets containing such excipients as starch or lactose, or inthe form of elixirs or suspensions containing flavoring or coloringagents. In the case of animals, the compounds of the present inventionare advantageously contained in an animal feed or drinking water. Forparenteral injection, they may be used in the form of a sterile aqueoussolution which may contain other solutes, for example, enough salt orglucose to make the solution isotonic. Other active compounds, includingNSAIDS (non-steroidal antiinflammatory drugs) may be administered alongwith the compounds of the present invention.

The following non-limiting Preparations and Examples are illustrative ofthe preparation of compounds of the present invention. All meltingpoints referred to in the Preparations and Examples are uncorrected.

PREPARATION OF STARTING MATERIALS

The compounds described in Table I were used in preparing compounds ofthe present invention. Unless a reference is given, the compounds arecommercially available:

                  TABLE 1                                                         ______________________________________                                         ##STR7##                                                                      ##STR8##                                                                     Compound                                                                      Number  Formula  X        R.sup.1                                                                           R.sup.5                                                                           Reference                                   ______________________________________                                        P1      IX       S        H   H   Commercial material                         P2      IX       O        H   H   Commercial material                         P3      IX       CH.sub.2 H   H   Commercial material                         P4      IX       CH.sub.2 H   F   J. Indian Chem. Soc.,                                                         38, 877 (1961)                              P5      IX       CH.sub.2 F   F   J. Am. Chem. Soc.,                                                            63, 1563 (1941)                             P6      IX       CH.sub.2 CH.sub.2                                                                      H   H   Commercial material                         P7      X        S        H   H   Acad. Sc. Paris, 265,                                                         758 (1967)                                  P8      X        O        H   H   J. Het. Chem., 6, 809                                                         (1963)                                      P9      X        CH.sub.2 CH.sub.2                                                                      H   H   British Patent 897,052                      P10     XI       S        H   H   Acad. Sc. Paris, 265,                                                         758 (1967)                                  P11     XI       CH.sub.2 CH.sub.2                                                                      H   H   British Patent 897,052                      ______________________________________                                    

PREPARATION 12-Fluoro-3-trifluoromethyl-N-chloroacetyl-1,4-dihydrobenzothiazine

2-Fluoro-3-trifluoromethyl-1,4-dihydrobenzothiazine prepared asdescribed in Chemistry Letters, 167 (1983), was reacted withchloroacetyl chloride to yield the title compound. ¹ H NMR (CDCl₃, 60MHz), ppm (δ): 4.3 (S, 2H), 6.9-7.0 (m, 4H).

Similarly prepared were the following:

2-fluoro-N-chloroacetylacridan (m.p. 121°-124° C.);

2,7-difluoro-N-chloroacetylacridan (m.p. 128°-131° C.);

1,2,3,4-tetrahydro-6-fluoro-N-chloroacetylquinoline [¹ H NMR(CDCl₃, 60MHz), ppm (δ) 2.0 (m, 2H), 2.7 (m, 2H), 3.7 (m, 2H), 4.2 (s, 2H),6.7-7.2 (m, 3H)];

2,3-dihydro-3,7-dimethyl-N-chloroacetyl-1,4-benzoxazine and3,7-dimethyl-N-chloroacetyl-1,2,3,4-tetrahydrobenzoxazine (m.p.59°-61°).

PREPARATION 22-Fluoro-3-trifluoromethylpyrrolo[1,2,3-de]-1,4-benzothiazin-5(6H)-one

A mixture of the title compound of Preparation 1 (3.11 g) and anhydrousaluminum chloride (4.0 g) was heated in an open beaker at 150° C. for0.5 hours. After evalution of gaseous hydrogen chloride ceased, theresidue was cooled to room temperature and then quenched with a mixtureof 10 ml concentrated HCl and 200 ml of ice water. The resulting darkbrown solid was extracted with ethyl acetate (2×100 ml) and the organicextract was evaporated to dryness. The residue was purified bychromatography over silica gel, using methylene chloride as the eluant,to obtain the title compound as a white crystalline solid, m.p.128°-130° C.

Similarly prepared were the following:

    ______________________________________                                         ##STR9##                                                                                                            Reference or                                                                  Melting                                Compound                                                                              Formula  X       R.sup.1                                                                            R.sup.3                                                                            R.sup.5                                                                           Point °C.                       ______________________________________                                        P12     VIII     S       H    H    --  85-87                                  P13     VIII     CH.sub.2                                                                              H    H    --  *                                      P14     VII      O       CH.sub.3                                                                           CH.sub.3                                                                           --  96-98                                  P15     VIII     CH.sub.2                                                                              F    H    --  119-121                                P16     IX       O       H    --   H   182-183                                P17     IX       CH.sub.2                                                                              H    --   H   175-176                                P18     IX       CH.sub.2                                                                              H    --   F   134-138                                P19     IX       CH.sub.2                                                                              F    --   F   206- 208                               P20     VIII     CH.sub.2                                                                              CH.sub.3                                                                           --   --  *                                      ______________________________________                                         *British Patent 1,394,373                                                

PREPARATION 35,6-Dihydro-2-fluoro-5-oxo-3-trifluoromethylpyrrolo[1,2,3-de]-1,4-benzothiazine-6-carboxylicacid, ethyl ester

To a solution of sodium ethoxide prepared from sodium metal (0.35 g) andethanol (30 ml) was added the title compound of Preparation 2 (1.37 g)followed by diethyl carbonate (1.77 g). The solution was heated at 65°C. for 3 hours. The reaction mixture was cooled, poured into ice water,acidified with dilute HCl to pH about 3 and the resulting solidcollected by filtration. ¹ H NMR(CDCl₃, 60 MHz) , ppm (δ): 1.3 (t, J=8Hz, 3H), 4.1 (q, J=8 Hz, 2H), 4.3 (s, 1H, 6.9-7.2 (m, 3H).

Similarly, prepared were the following:

ethyl-5,6-dihydro-pyrrolo[1,2,3-de]-tetrahydro-1,4-benzothiazine-5(6H)-one-1-carboxylate [¹ H NMR (CDCl₃, 60 MHz), ppm (δ): 1.3 (t, J=8 Hz,3H) , 3.0 (m, 2H) , 3.9-4.2 (m, 5H) , 6.9-7.1 (m, 3H)];

ethyl-2-oxo-5,6-dihydro3,8-dimethyl-pyrrolo[1,2,3-de]tetrahydro-1,4-benzoxazin-5(6)-one-1-carboxylate[¹ H NMR (CDCl₃, 60 MHz), ppm (δ): 1.2 (t, J=8 Hz, 3H), 1.5 (d, J=12 Hz,3H), 2.4 (s, 3H), 4.1 (m, 3H), 4.2 (m, 2H), 6.8 (m, 2H)];

ethyl-2-oxo-1,2,5,6-tetrahydro-4-H-pyrollo-[3,2,1-J]quinoline-1-carboxylate[¹ HNMR(CDCl₃, 60 MHz) , ppm (δ): 1.5 (t, J=7Hz, 3H), 2.1 (m, 2H), 2.9(m, 2H), 3.9 (t, J=7 Hz, 2 H), 4.2 (m, 2H), 7.2 (m, 3H)];

ethyl-2-oxo-7-fluoro-1,2,5,6-tetrahydro-4-H-pyrollo[3,2,1-iJ]quinoline-1-carboxylate (m.p. 118°-120° C.); and

ethyl-2-oxo-7-methyl-1,2,5,6-tetrahydro-4-H-pyrollo[3,2,1-iJ]quinoline-1-carboxylate[¹ HNMR(CDCl₃, 60 MHz), ppm. (δ): 1.5 (t, J=7 Hz, 3H), 2.0 (m, 2H ) ,2.4 (5,3H), 2.9(m, 2H) , 3.9 (t, J=7 Hz; 2H), 4.2 (m, 2H) , 7.2 (dd,J=2, 2H)].

PREPARATION 4 Methylpyrrolo[3,2,1-kl]phenoxazine-1-one-2-carboxylate

To a slurry of sodium hydride (0.39 g) in 20 ml of DMF(dimethylformamide) was added pyrrolo[3,2,1-kl]phenoxazine (1.4 g),prepared as described according to Preparation 2, and the resulting darkred solution was stirred at room temperature for 0.5 hours. To thissolution, was added methyl chloroformate (0.95 g), dropwise, over aperiod of 10 minutes. The reaction mixture was stirred for 2 hours atroom temperature, and it was then poured onto ice water (200 ml). Theresulting mixture was then acidified to pH 2.0 with concentrated HCl andthe mixture was then extracted with methylene chloride (200 ml). Theextract was washed with water, dried and evaporated to dryness to yieldthe title compound as a solid (0.06 g; m.p. 124°-127° C.).

PREPARATION 5 Ethyl 6H-pyrido[3,2,1-de]acridin-1(2H)-one 10 carboxylate

To a freshly prepared solution of sodium ethoxide in ethanol (from 0.35g sodium metal and 10 ml ethanol) was added 6H-pyrido[3,2,1-de]acridin-1(2H)-one (1.2 g) portionwise over a period of 10 minutes. To theresulting dark red solution was slowly added diethyl carbonate (1.77 g)and the solution was then refluxed for 3 hours. The reaction mixture wascooled, acidified to pH 2 with concentrated HCl and then extracted withmethylene chloride. The organic extract was washed with water and wasthen collected, dried and evaporated to dryness to obtain a light ambersolid (1.8 g; m.p. 113°-118° C.).

PREPARATION 6

Following the method of Preparation 4 or Preparation 5, the followingcompounds were prepared:

    ______________________________________                                         ##STR10##                                                                                                     Melting                                      Compound                                                                              X         R.sup.1                                                                             R.sup.5                                                                           R.sup.6                                                                            Point °C.                                                                     Method                                ______________________________________                                        P21     S         H     H   CH.sub.3                                                                           144-145                                                                              Preparation 4                         P22     CH.sub.2  H     H   CH.sub.3                                                                           89-92  Preparation 4                         P23     CH.sub.2  F     F   C.sub.2 H.sub.5                                                                    134-136                                                                              Preparation 5                         P24     CH.sub.2CH.sub.2                                                                        H     H   CH.sub.3                                                                           121-123                                                                              Preparation 4                         ______________________________________                                    

EXAMPLE 11,2-Dihydro-N-(2,4-difluorophenyl)-1-oxopyrrolo[3,2,1-kl]phenothiazine-2-carboxamide

To a suspension of sodium hydride (0.14 g) in DMF (10 ml) was addedpyrrolo[3,2,-1kl]phenothiazine-1-one (0.48 g) and to the resultingsolution was slowly added 2,4-difluorophenyl isocyanate (0.31 g) . Thereaction mixture was stirred for 12 hours and then poured onto ice water(50 ml). The resulting mixture was acidified to pH 2.0 with 6N HCl andthe precipitated solid was collected and then air dried-to yield thetitle compound (2.84 g). A sample recrystallized from methylene chloridehad a m.p. of 208°-209° C.

EXAMPLE 2

1,2-Dihydro-N-[2-pyridyl]-1-oxopyrrolo[3,2,1-kl]phenothiazine-1-carboxamide

A mixture of methyl pyrrolo[3,2,-1-kl]phenoxazine-1-one-2-carboxylate(0.7 g) , 2 aminopyridine (0.28 g) and xylene (20 ml) was heated underreflux for 0.5 hours. It was then cooled to room temperature and theprecipitated yellow solid was collected by filtration (0.64 g, m.p.224°-225° C.).

EXAMPLES 3-5

Starting, in each case, from the corresponding lactam or ester,compounds E1, E2, E11-E14, E18-E21, and E43-E46, described below, wereprepared by the method of Example 1 and compounds E3-E10, E15-E17,E22-E42, and E47-E83, described below, were prepared by the method ofExample 2.

EXAMPLE 3

    ______________________________________                                         ##STR11##                                                                    Com-                                                                          pound                                Melting                                  Number X        R.sup.1                                                                             R.sup.5                                                                           R.sup.2    Point °C.                         ______________________________________                                        E1     S        H     H   4-Cl-phenyl                                                                              247-248                                  E2     S        H     H   2-F,4-F-phenyl                                                                           208-209                                  E3     S        H     H   phenyl     236-239                                  E4     S        H     H   2-pyridyl  228-229                                  E5     S        H     H   2-thiazolyl                                                                              203-205                                  E6     S        H     H   2-thiazolyl-5-CH.sub.3                                                                   218                                      E7     S        H     H   5-isothiazolyl-3-                                                             methyl     228-231                                  E8     S        H     H   2-F,6-F-phenyl                                                                           237-241                                  E9     S        H     H   2-F,5-F-phenyl                                                                           207-208                                  E10    S        H     H   2[1,3,4-thiazolyl]-                                                                      186-188                                                            5-CF.sub.3                                          E11    O        H     H   4-Cl-phenyl                                                                              268-270                                  E12    O        H     H   4-F-phenyl 254-256                                  E13    O        H     H   phenyl     254                                      E14    O        H     H   2-F,4-F-phenyl                                                                           238-239                                  E15    O        H     H   2-pyridyl  224-225                                  E16    O        H     H   3-isoxozolyl-5-                                                                          197-198                                                            CH.sub.3                                            E17    CH.sub.2 H     H   2-thiazolyl                                                                              206-208                                  E18    CH.sub.2 H     H   4-F-phenyl 224-226                                  E19    CH.sub.2 H     H   2-F,4-F-phenyl                                                                           186                                      E20    CH.sub.2 H     H   phenyl     209                                      E21    CH.sub.2 H     H   4-Cl-phenyl                                                                              235-237                                  E22    CH.sub.2 H     H   2-thiazolyl                                                                              231-234                                  E23    CH.sub.2 H     H   2-pyridyl  209                                      E24    CH.sub.2 H     H   2-thiazolyl-5-CH.sub.3                                                                   231-232                                  E25    CH.sub.2 H     H   5-isothiazolyl-3-                                                                        211-213 (dec.)                                                     CH.sub.3                                            E26    CH.sub.2 H     H   2-F,6-F-phenyl                                                                           264-265                                  E27    CH.sub.2 H     H   2-pyridyl-6-CH.sub.3                                                                     232-233                                  E28    CH.sub.2 H     H   3-isoxozolyl-5-                                                                          198 (dec.)                                                         CH.sub.3                                            E29    CH.sub.2 H     H   3-1H-pyrazolyl                                                                           248-250                                  E30    CH.sub.2 H     H   2-1H-imidazolyl                                                                          268 (dec.)                               E31    CH.sub.2 H     H   2-pyrimidinyl                                                                            219-221                                  E32    CH.sub.2 H     H   2-(1,2,4-thiadia-                                                                        204-205 (dec.)                                                     zolyl)-5-CF.sub.3                                   E33    CH.sub.2 H     F   5-isothiazolyl-3-                                                                        203-205                                                            CH.sub.3                                            E34    CH.sub.2 H     F   2-[1,2,4-thiadia-                                                                        211-214                                                            zolyl]-5-phenyl                                     E35    CH.sub.2 H     F   2-F,4-F-phenyl                                                                           222- 223                                 E36    CH.sub.2 H     F   2-F,5-F-phenyl                                                                           184-186                                  E37    CH.sub.2 H     F   2-thiazolyl                                                                              168-174 (dec.)                           E38    CH.sub.2 H     F   2-[1,3,4-thiadia-                                                                        208-210                                                            zolyl]                                              E39    CH.sub.2 F     F   2-pyridyl  246-248                                  E40    CH.sub.2 F     F   2-thiazolyl                                                                              199-200                                  E41    CH.sub.2 F     F   2-thiazolyl-5-CH.sub.3                                                                   223 (dec.)                               E42    CH.sub.2 F     F   5-isothiazolyl-3-                                                                        233 (dec.)                                                         CH.sub.3                                            E43    CH.sub.2 CH.sub.2                                                                      H     H   2-F,4-F-phenyl                                                                           217-218                                  E44    CH.sub.2 CH.sub.2                                                                      H     H   4-Cl-phenyl                                                                              194-196                                  E45    CH.sub.2 CH.sub.2                                                                      H     H   4-F-phenyl 224-225                                  E46    CH.sub.2 CH.sub.2                                                                      H     H   phenyl     224-225                                  E47    CH.sub.2 CH.sub.2                                                                      H     H   2-pyridyl  202-204                                  E48    CH.sub.2 CH.sub.2                                                                      H     H   2-thiazolyl                                                                              248-249                                  E49    CH.sub.2 CH.sub.2                                                                      H     H   3-methylthioethyl                                                                        158-159                                  E50    CH.sub.2 CH.sub.2                                                                      H     H   3-isoxazolyl-5-CH.sub.3                                                                  168-169                                  E51    CH.sub.2 CH.sub.2                                                                      H     H   2-thiazolyl-4CH.sub.3 -                                                                  261-262                                                            5CH.sub.3                                           E52    CH.sub.2 CH.sub.2                                                                      H     H   2-benzothiazolyl                                                                         167-168                                  E53    CH.sub.2 CH.sub.2                                                                      H     H   2-thiazolyl-5-CH.sub.3                                                                   234-236                                  ______________________________________                                    

EXAMPLE 4

    ______________________________________                                         ##STR12##                                                                    Compound                                                                      Number/                                   Melting                             Formula X     R.sup.1                                                                              R.sup.2    R.sup.4                                                                            R.sup.3                                                                            Point °C.                    ______________________________________                                        E54/II  O     CH.sub.3          CH.sub.3                                                                           H    205-206                             E55/II  O     CH.sub.3                                                                             2-pyridyl  CH.sub.3                                                                           H    168-169                             E56/II  O     CH.sub.3                                                                             phenyl     CH.sub.3                                                                           H    190-191                             E57/II  O     CH.sub.3                                                                             2F,4F-phenyl                                                                             CH.sub.3                                                                           H    181-183                             E58/II  O     CH.sub.3                                                                             2-thiazolyl                                                                              CH.sub.3                                                                           H    172-174                             E59/II  O     CH.sub.3                                                                             2-benzothia-                                                                             CH.sub. 3                                                                          H    184-185                                                  zolyl                                                    E60/II  O     CH.sub.3                                                                             2[1,3,4-thia-                                                                            CF.sub.3                                                                           H    186-188                                                  diazolyl]-5-                                                                  CF.sub.3                                                 E61/II  O     CH.sub.3                                                                             2-oxazolyl-5-                                                                            CH.sub.3                                                                           H    194-196                                                  CH.sub.3                                                 E62/II  O     CH.sub.3                                                                             5-isothia- CH.sub.3                                                                           H    219-220                                                  zolyl-3-CH.sub.3                                         E63/III S     H      2-thiazolyl                                                                              F    CF.sub.3                                                                           211                                 E64/III S     H      2-F,4-F-phenyl                                                                           F    CF.sub.3                                                                           214-216                             E65/III S     H      5-isothia- F    CF.sub.3                                                                           240-242                                                  zolyl-3-CH.sub.3                                         ______________________________________                                    

EXAMPLE 5

    ______________________________________                                         ##STR13##                                                                    Compound                           Melting                                    Number   R.sup.1 R.sup.2           Point °C.                           ______________________________________                                        E66      H       2-Cl,4-Cl-phenyl  199-200                                    E67      H       phenyl            175-176                                    E68      H       2-pyridyl         246-247                                    E69      H       3-methyl-2-pyridyl                                                                              213-214                                    E70      H       4-F-phenyl        191-194                                    E71      H       2-thiazolyl       208-210                                    E72      H                         164-168                                    E73      H       2-Cl,5-Cl-phenyl  187-189                                    E74      H       3-Cl,4-Cl-phenyl  200-201                                    E75      H       4-Br-phenyl       206-207                                    E76      H       2-F,5-F-phenyl    176-180                                    E77      H       2-F,4-F-phenyl    174-175                                    E78      H       4-methyl-2-thiazolyl                                                                            202-205                                    E79      H       4,5-dimethyl-2-thiazolyl                                                                        249-252                                    E80      F       2-thiazolyl       213-214                                                                       (dec.)                                     E81      CH.sub.3                                                                              2-pyridyl         189-190                                    E82      CH.sub.3                                                                              5-isothiazolyl-3-methyl                                                                         174-177                                    E83      CH.sub.3                                                                              2-benzothiazolyl  178-180                                    ______________________________________                                    

EXAMPLE 6

The compounds numbered E1-E83 and the compounds of Examples 1 and 2 wereassayed according to the method of Jakschick et al. described above. Thecompounds were found to have inhibitory activity against cyclooxygenaseor 5-lipoxygenase or both.

We claim:
 1. A compound of the formula ##STR14## wherein the broken linerepresents an optional double bond; X is S; R¹ is selected from thegroup consisting of hydrogen, halogen, C₁ -C₆ alkoxy, C₁ -C₆ alkanoyl,C₁ -C₆ alkyl, and trifluoromethyl; R² is selected from the groupconsisting of phenyl, substituted phenyl, heterocyclic selected from thegroup consisting of pyridyl, thiazolyl, oxazolyl, isoxazolyl, pyrazolyl,isothiazolyl, pyrimidinyl, thiadiazolyl, and benzothiazolyl, andsubstituted heterocyclic groups, said substituted phenyl and substitutedheterocyclic groups being substituted with 1 or 2 substituentsindependently selected from the group consisting of C₁ -C₆ alkyl,trifluoromethyl, and halogen;R³ and R⁴ are independently selected fromthe group consisting of hydrogen, halogen, C₁ -C₆ alkyl, andtrifluoromethyl, or R³ and R⁴ taken together with the carbon atoms towhich they are attached form a six-membered carbocyclic aromatic ring,said aromatic ring being optionally substituted with one or twosubstituents selected from the group consisting of halogen, C₁ -C₆alkyl, and trifluoromethyl; or a pharmaceutically acceptable saltthereof.
 2. A compound according to claim 1, wherein said heterocyclicgroups are substituted with one or two substituents selected from thegroup consisting of halogen, C₁ -C₆ alkyl, and trifluoromethyl.
 3. Acompound according to claim 1, said compound being a compound of theformula ##STR15## wherein R¹, R² and X are as defined above and R⁵ isselected from the group consisting of hydrogen, halogen, C₁ -C₆ alkyl,and trifluoromethyl, or a pharmaceutically acceptable salt thereof.
 4. Acompound according to claim 3, wherein R¹ is hydrogen or fluorine; R² isphenyl, 2,4-difluorophenyl, pyridinyl, thiazolyl, benzothiazolyl,isothiazolyl, or isoxazolyl, and R⁵ is hydrogen or fluorine.
 5. Acompound according to claim 1, said compound being a compound of theformula ##STR16## wherein R¹, R², R³ and X are as defined above, or apharmaceutically acceptable salt thereof.
 6. A compound according toclaim 5, wherein R¹ is hydrogen, fluoro, or trifluoromethyl; R² isphenyl, 2,4-difluorophenyl, pyridyl, thiazolyl, isothiazolyl,benzothiazolyl or isoxazolyl; R³ is hydrogen, fluoro, ortrifluoromethyl; and X is O, S or CH₂.
 7. A compound according to claim1, said compound being a compound of the formula ##STR17## wherein R¹,R², R³, R⁴ and X are as defined above, with the proviso that R³ and R⁴do not form a carbocyclic aromatic ring, or a pharmaceuticallyacceptable acid addition salt thereof.
 8. A compound according to claim7, wherein R¹ is hydrogen.
 9. A compound according to claim 8, whereinR³ is trifluoromethyl and R⁴ is fluorine.
 10. A compound according toclaim 1, said compound being selected from the group consistingof1,2-dihydro-N-phenyl-1-oxopyrrolo[3,2,1-kl]-phenothiazine-2-carboxamide;1,2-dihydro-N-(2,4-difluorophenyl)-1-oxopyrrolo[3,2,1-kl]phenothiazine-2-carboxamide;1,2-dihydro-N-(2-pyridyl)-1-oxopyrrolo[3,2,1-kl]-phenothiazine-2-carboxamide;and1,2-dihydro-N-(2-thiazolyl)-1-oxypyrrolo[3,2,1-kl]-phenothiazine-2-carboxamide;andthe pharmaceutically acceptable salts thereof.
 11. A method of treatinginflammation comprising administering to a patient in need of suchtreatment an effective amount of a compound of claim
 1. 12. Apharmaceutical composition for the treatment of inflammation comprisingan effective amount of a compound of claim 1 and a pharmaceuticallyacceptable carrier.